Inflammatory Bowel Diseases (IBD) affect over 1.3 million people in North America, and are associated with significant morbidity and mortality. The causes of IBD remain unknown, and chronic medicinal therapy is necessary to manage them. The long term objectives of the proposal are to validate drugs that target the 5- opioid receptor (MOR) as potential therapeutics for IBD, and to determine their mechanisms of action. Preliminary data shows that MOR agonist ameliorates DSS colitis. However, the mechanism of action of DSS- mediated protection remains unknown. Prelminary studies also show MOR-induced IL-22 mRNA expression in vivo. IL-22 is a potent inducer of STAT3 phosphorylation, and other prelminary data shows the MOR agonist induces STAT3 activation in cultured enterocytes. Consequently, we hypothesize that the activation of MOR signaling plays a beneficial role in DSS-induced colitis through an up-regulation of STAT3 signaling in enterocytes. Because both IECs and mononuclear immune cells respond to MOR agonist, and dendritic cells (DCs) produce the STAT3 activating cytokine IL-22, we will use tissue-specific ablation of MOR to dissect the cell compartment(s) necessary for MOR-protective signaling against colonic injury. The specific aims of this proposal are to: 1) identify the role of IL-22/STAT3 signaling in MOR-mediated cyto-protective function; and 2), identify the cell compartment(s) responsible for the MOR-mediated protective function. The impact and molecular mechanisms of MOR-mediated signaling on IBD will be determined using acute experimental models of intestinal injury (DSS-colitis and ischemia/reperfusion injury) applied to wild-type and tissue-specific, gene-deficient mice. This work will be complemented with a series of molecular and cellular biology studies as well as molecular pharmacology experiments. PUBLIC HEALTH RELEVANCE: Relevance to public health: IBD patients often become non-responsive to their therapies over time, leaving surgery as their only recourse. Consequently, new and better therapies are desperately needed for patients, to both maintain remission and to stave off the associated risks and morbidity of surgery. This work has the potential to bring forward new therapeutic modalities through activation of mu opioid receptor signaling.